Stochastic Mesocortical Dynamics and Robustness of Working Memory during Delay-Period

Abstract

The role of prefronto-mesoprefrontal system in the dopaminergic modulation of working memory during delayed response tasks is well-known. Recently, a dynamical model of the closed-loop mesocortical circuit has been proposed which employs a deterministic framework to elucidate the system’s behavior in a qualitative manner. Under natural conditions, noise emanating from various sources affects the circuit’s functioning to a great extent. Accordingly in the present study, we reformulate the model into a stochastic framework and investigate its steady state properties in the presence of constant background noise during delay-period. From the steady state distribution, global potential landscape and signal-to-noise ratio are obtained which help in defining robustness of the circuit dynamics. This provides insight into the robustness of working memory during delay-period against its disruption due to background noise. The findings reveal that the global profile of circuit’s robustness is predominantly governed by the level of D1 receptor activity and high D1 receptor stimulation favors the working memory-associated sustained-firing state over the spontaneous-activity state of the system. Moreover, the circuit’s robustness is further fine-tuned by the levels of excitatory and inhibitory activities in a way such that the robustness of sustained-firing state exhibits an inverted-U shaped profile with respect to D1 receptor stimulation. It is predicted that the most robust working memory is formed possibly at a subtle ratio of the excitatory and inhibitory activities achieved at a critical level of D1 receptor stimulation. The study also paves a way to understand various cognitive deficits observed in old-age, acute stress and schizophrenia and suggests possible mechanistic routes to the working memory impairments based on the circuit’s robustness profile.

Understanding the role of alterations in cortical D1 receptor sensitivity in shaping working memory maintenance through mesocortical dynamics

“…Notably, the post-peak set involves higher z DR as well as an inhibition-dominated cortical dynamics whereas the pre-peak set involves relatively lesser z DR and an excitation-dominated cortical dynamics (Fig 2a). These observations have a remarkable similarity with that obtained in the earlier theoretical studies (Durstewitz et al 1999;Brunel and Wang 2001;Deco and Rolls 2003;Okimura et al 2015;Reneaux et al 2015) involving change in the D1R stimulation level assumed to occur through alteration in cortical DA content during delay. However, the present investigation further shows that these specific features also remain identically conserved across alterations in D1R-sensitivity.…”

“…The present model provides quantitative profiles of the various measurable entities of the mesocortical dynamics in close association with their experimentally known estimates. Further, a stochastic formulation of the mass model Reneaux et al 2015 is utilized to gain features of robustness of the WM maintenance during delay under the physiologically-relevant situation of noisy mesocortical dynamics.…”

“…Further, the mesocortical dynamics is constantly affected by the various natural sources of noise in the neural system (Faisal et al 2008). Therefore, the stochastic framework of the mesocortical dynamics Reneaux et al 2015 is given by,…”

“…For this, the steady-state marginal probability distributions of the state-variables P st (x), where x ∈ {x P N , x IN , x DN , y DA , z DR }, are obtained from the numerical simulation of the stochastic mesocortical dynamics using the Euler-Maruyama scheme (Kloeden and Platen 1992) with a fixed time-step ∆t. Consequently, a joint probability distribution P st (x P N , z DR ) is obtained over the state-space x P N -z DR and the global potential landscape, U (x P N , z DR ), of the stochastic mesocortical dynamics is constructed as (Reneaux et al 2015),…”

“…Here, with decrease in D1R-sensitivity, the associated optimal range of DA appears more and more unapproachable by the normal levels of DA-releasability of the mesocortical projections. The situation becomes more severe as the DA-releasability also exhibits a decline in ageing (Goldman-Rakic and Brown 1981;de Keyser et al 1990;Suhara et al 1991;Reneaux et al 2015). Therefore, ageing may end up either in a complete loss of WM maintenance or a poor WM maintenance depending on the severity of D1Rs depletion as well as decline in the DA-releasability.…”